Clinical manifestations of leishmaniasis in the Americas range from self-healing ulcerative skin lesions through severe mutilating mucocutaneous disease to widely disseminated skin or visceral involvement. Leishmanial parasites in animal hosts are obligatory intracellular organisms with the macrophage as the exclusive cell target. Cell-mediated immune mechanisms are of prime importance in successful control of the parasites within a given host. Mice provide useful models for studying leishmanial infections since disease patterns, mimicking those seen in human infections, can readily be observed with different inbred mouse stains. This proposal aims at defining specific events in the host-parasite interactions that would explain this spectrum of disease expression. To accomplish this aim, the study will compare infections in two mouse strains with markedly different susceptibility patterns to a South American leishmanial parasite. In addition, there will be a comparison of infections in the BALB/c mouse of two leishmanial strains to which differences in susceptibility exist. The methodology employed will include in vitro tissue culture of macrophages and parasites, as well as in vivo murine leishmanial infections. In particular, the interaction of promastigotes with murine macrophages in vitro and conditions favoring either parasite propagation or macrophage killing will be defined. In addition, delayed type hypersensitivity, lymphocyte proliferation responses, antibody-dependent cytotoxicity and quantitative parasitologic measures will be followed in experimental infection of inbred strains. The role of cross-immunity between animals infected with either of two strains of American leishmanial parasites will be determined. The development of suppressor cells will be followed, and the role of the macrophage as the antigen-presenting cell will be outlined. Apart from providing data on the immunobiology of leishmanial infections, this study will provide relevant data for understanding specific principles of cell-mediated immunity. Long-term objectives include definition at the molecular level of the antigenic and physiologic differences between the Maria and Isabel strains and clarification of the way macrophages from BALB/c mice process and present these antigens. Furthermore, the information gained here will be applied to future human studies.